EASD: Additional Benefits of Nitric Oxide in Diabetes Management

Past studies have shown that nitric oxide (NO) plays an important role in regulating insulin clearance; however, it is uncertain whether the control of insulin clearance is achieved through hepatic mechanisms alone or involves hypothalamic regulation as well. Because the hypothalamus is a critical regulator in energy metabolism and endocrine functions, a team of researchers conducted a study in which they theorized that NO produced in the central/hypothalamic axis regulated insulin clearance and, therefore, also controlled peripheral insulin bioavailability. They discovered that there was a significant inverse relationship between NO produced in the paraventricular nucleus (PVN) and systemic insulin clearance, so they then theorized that the regulation of insulin clearance was mediated by PVN NO. The metabolic effects of PVN NO-mediated regulation of insulin clearance were unknown, but the researchers hypothesized that PVN NO also modulated hepatic glucose and lipid metabolism.

The researchers performed brain surgery on male Wistar rats using a stereotaxic apparatus for implantation of the double cannulas in order to deliver nucleus specific infusion in the PVN region. The coordinates after the bregman localization were AP: -1.8mm, Lat: +/- 0.4mm, DV: -8.0mm. The control animals were given a bolus infusion of 2uL of saline, while the experimental animals were given a bolus infusion of 250ug/2uL of L-NAME. The infusion was performed once on each side of the brain only on the day of the experiment. Then, an oral glucose tolerance test (2g/kg) was performed. The livers of the animals were removed and kept at -80º in order to obtain protein extraction and analysis of glucose and lipid metabolism-related enzymes by immunoblotting.

The results of the study showed that a reduction in PVN NO caused changes in insulin signaling and glucose and lipid metabolism. IRS-1 and AKT expression and phosphorylation declined, which indicated that there was decreased glucose uptake by the liver. Reduced PVN NO levels also lead to decreased lipogenic enzymes, including ACC, FAS, ATP citrate lyase and pATP citrate lyase, which diminished the hepatic non-esterified fatty acids (NEFA) content. Hepatic DGAT expression increased, and the researchers believe that this was a result of the decrease in NEFA. PVN NO depletion did not cause hepatic TG levels to diminish, and this could possibly be due to DGAT up-regulation.

In conclusion, these findings supported the hypothesis that increased PVN NO led to decreased insulin clearance and de novo lipogenesis stimulation. Therefore, it was deduced that hypothalamic NO signaling affected the regulation of hepatic lipid metabolism.

Practice Pearls:

The increased production of PVN NO resulted in decreased insulin clearance and increased peripheral insulin bioavailabilty.

In addition, an increase in PVN NO also caused a stimulation of de novo lipogenesis.

As a result, it can be concluded that hypothalamic NO signaling plays a role in regulating hepatic lipid metabolism